Diammonium compounds



United States Patent @tiice 2,798,205 Patented May 10, 1955 1 2,708,206DIAMMGNIUM COMPOUNDS Emil Girod, Riehen, near Basel, and Franzl-Iiiiiiger, Basel, Switzerland, assignors to J. R. Geigy A. G., Basel,Switzerland No Drawing. Application April 20, 1953, Serial No. 349,947Claims priority, application Switzerland April 22, 1952 3 Claims. (Cl.260482) This invention concerns new diammonium compounds of the generalformula:

represents low molecular dialkylamino groups, piperidino,methylpiperidino, pyrrolidino, methylpyrrolidino, morpholino ormethyl-morpholino groups, R represents low molecular alkyl radicals, nrepresents a whole number from 8 to 20, m represents a whole number from2 to 4, and An represents a monovalent anion, in particular of halogenhydrohalic acids or a normal equivalent of a polyvalent anion.

Such compounds can be produced by reacting bisarninoalkoxyalkanes of thegeneral formula:

R R N(CH2)m O '(CH2)nO(CHi)mN R R. II with two mols of halogen aceticacid alkyl esters of the general formula:

HalCH2-COO-R' Ill wherein R R, m and n have the meanings given above andHal represents a halogen atom.

The ditertiary bis-aminoalkoxy-alkanes of the general Formula IInecessary as starting materials can be obtained for example by reactinga,w-alkane diols of the general formula preferably in the form of theirmetal compounds (alcoholates) with 2 mols of tertiary amine-alkylhalides of the general formula N(CHz),,.Hal

R or by reacting oc,w-dihalgen alkanes of the general formula Hal-( CH2n-Hal with 2 mols of tertiary aminoalcohols of the general formulaN(GH2)mOH R also advantageously in the form of their metal compounds.The second process is to be preferred when the corresponding tertiaryaminoalkyl halides, which are necessary in the first process are veryunstable, such as e. g. for the production of ditertiarybis-(5-aminobutoxy)- alkanes.

The following can be named for example as ditertiarybis-aminoalkoxy-alkanes of the general Formula II:

crystals.

1,8 bis (,8 dimethylamino-ethoxy)octane B. P.0.05

1,8-bis-(fi-diethylamino-ethoxy)-octane H. Ross 156-l581,8-bis-('y-diethylamino-propoxy)-octane B. Peas 16.3

1,9 bis 8 dimethylamino ethoXy)-nonane B. P.o.0s

1,9 bis (5 diethylamino ethoxy)-nonane, B. Rona 1,10 bis (Bdimethylamino ethoxy)-decane, B. P.o.o4

1,10 bis (,8 diethylamino ethoxy)-decane B. Prune LIO-biS-(BpyrmlidinoethoXy)-decane, dihydrobromide 1,IO-bis-(B-piperidino-ethoxy)-decane, B.1 .0.04 l59-168 1,10-bis-(finiorpholino-ethoxy) -decane B. P4115 2l12l5l-(fl-dimethylamino-ethoxy) 10 ('y-diethylamino-propoXy)-decane B.P.u.o7 l53-158 l-(,B-diethylaminoethoxy) 10 'y(dimethylaminopropoXy)-decane, B. P.o.os 144149 1,10-bis-(yd'unethylamino propoxy)-decane, B. P.u.o2

1,10 bis (y diethylaminopropoxy) decane, B. Rona 1,10 bis ('ydibutylamino-propoxy)-decane, B. P.o.o9

1,11 bis (B-dimethylamino-ethoxy)-undecane, B. P.o.1a

1, l2-bis- -diethylamino-propoxy) -dodecane 1,14-bis-(B-diethylamino-ethoxy) -tetradecane, B. P.o.oo1

approx.

1,1S-bis-(B-dimethylamino-butoxy)-pentadecane1,16-bis-(,S-dimethylamino-ethoxy)-hexadecane1,1S-bis-(,B-diethylamino-ethoxy)-octadecane 1 ,20-bis-(,B-dimethylamino-ethoxy) -eicosane The following can be used forexample as halogen acetic acid esters of the general formulaHal-CI-Iz-CO-OR' wherein R represents a low molecular alkyl radical,chloracetic acid and bromacetic acid methyl esters, -ethyl esters,-n-propyl-esters, -isopropyl esters, -n-butyl esters, -isobutyl esters,-sec. butyl esters, -n-amyl esters and -isoamyl esters and the heXylesters.

As the pharmacological activity of the salts according to this inventiondepends chiefly on the cation, the type of anion is of lesser importancefor the purpose of this invention. Only salts of such inorganic ororganic acids should be used for therapeutical purposes which are not inthemselves strongly toxic and so do not cause pharmacological sideeffects. In other respects, the choice of the anion depends on variousother factors such as cost of acid or of quaternating agent, facility ofreaction, capability to form crystals (possibility of purifying) andwater solubility of the products. The most suitable acid is easy to findfrom case to case by a few tests.

Compounds in which An i is different from Hale, (-OAO2-OR) or(Aryl-SO2O)9 are produced advantageously by later exchange of these forother anions.

The diquaternary salts are almost colourless compounds which crystalliseor sometimes they are in the form of yellow viscous oils. Particularlyorganic solvents or suitable mixtures thereof such as mixtures of thosewhich generally dissolve well like alcohols with those which do notdissolve so well such as acetone or ethyl acetate or those which onlydissolve slightly such as ether or benzene are suitable for theformation of In general, these salts dissolve well in water i with apractically neutral reaction.

The diammoniurn compounds produced according to the present inventioncan be used for pharmaceutical purposes. In particular they influencethe muscle tonus. They have an action similar to curare, some have aspasmolytic action also.

The following examples illustrate the invention further. Parts are givenas parts by weight, preferably in grammes. The relationship of parts byWeight to parts by volume is as that of grammes to cubic centimetres.The temperatures are in degrees centigrade.

' EXAMPLE 1 1,10 bis [,8 (dimethyl carbalkoxymethyl ammonium) -ethxy]-decane di bromides 1 mol of 1,10-bis-(,B-dirnethylaminoethoxy)-decane,mols of dry acetone and about 2.4 mols of bromacetic acid-alkyl ester(for particulars of amounts see table) are boiled for about 14 hoursunder reflux. After cooling, should the quaternary salts precipitate inan oily form, they are crystallised by first cooling and rubbing, thenfiltered oil under suction and if desired recrystal lised from hotbutanone with the addition of the alkanol corresponding to the alkylradical in the bromacetic acid alkyl ester and dried in the vacuum at50-60.

i i Produced from 3.16 parts of decane deriva- Alkyl radical gg g tiv;in 20 parts by 'volume of acetone 137 4 parts of bromacetic acid ethylester. 144 4.3 parts of bromacetic acid isoprcpyl ester.

79 4.3 parts ofbromacetic acid propyl ester. 97 4.7 parts of bromaceticacid butyl ester. 127-128 4.6 parts of bromacetic acid isobutyl ester.

110 4.6 parts of bromaeetic acid tert. butylester. 134-137 4.9 parts ofbromacetic acid hexyl ester.

EXAMPLE 2 1,10'- bis [13 (diethyl carbethoxymethyl ammo-,nium)-eth0xy]-decane dibromide 7.44 parts ofbis-,B-(diethylamino-ethoxy)-decane, parts by volume of dry ethylacetate and 8 parts of bromacetic acid ethyl ester are boiled underreflux for about 14 hours. The acetic ester is poured off from p theprecipitated quaternary salt, the latter is stirred with dry acetone andabs. methanol is added until a solution is formed. On standing at -5,the salt crystallises into big' clear crystals. The crystals arefiltered off under suction, Washed with acetone and abs. ether and driedat 40-50 in a high vacuum. The hygroscopic product melts at about 75.

The following can be produced for example in an analogous manner:

1,10 bis 6 (carbethcxymethyl methyl ethyl ammonium) -ethoxy] -decanedibromide 1,10 bis [5 (carbethoxymethyl pyrrolidinium)- ethoxyl-decanedibromide, M. P. 140

1,10 bis [[3 carbomethoxymethyl 2,5 dimethylpyrrolidinium) ethoxy]-decane dibromide 1,10 bis [,8 (carboproproxymethyl piperidinium)-ethoxy] -.decane dibromide 1,10 bis [B (carbohexyloxymethylmorpholinium)- V 1 ethoxyl-decane dibromide 1,10 bis [t3(carbomethoxymethyl 3,5 dimethylmorpholinium) -ethoxy] -decane dibromide1,10 bis 'y- (carbethoxymethyl dimethyl ammonium)-propoxy1-decanedibromide 1,10 bis [7. (carbornethoxymethyl diethylammonium)-propoxyJ-decane dibromide 7 1,10 bis [,8 (carbomethoxymethyldiethyl ammonium) -ethoxy] -decane dichloride 1,10 bis(carbomethoxymethyl dibutyl ammonium)-propoXy]-decane dibromide 1,10 bis[y (carbopropoxymethyl pyrrolidinium)- propoxy] -decane dibromide 1,10bis [5 (carbomethoxymethyl diethyl ammonium) -butoxyl -decane dibromide1,11 bis 3 (carboethoxyrnethyl dirnethylamrnoniurn)-ethoXy]-un ecanedibromide 1,11 bis [3 carboethoxymethyl diethyl ammoniurn -eth0xyl-undecane dibromide 1,12 bis [5 (carbomethoxymethyl dimethylammonium}-ethoxy-dodecane dibromide 1,12 bis [,8 (carbohexyloxyrnethyldimethyl pyrrolidinium) -ethoxy] -dodecane dibromide 1,12 bis [y(carbomethoxymethyl diethyl ammonium)-propoxyldodecane dibromide 1,13bis [f3 (carbethoxymethyl dimethyl ammonium) -ethoxy] -tridecanedibromide 1,14 bis [B (carbomethoxymethyl diethyl ammonium -ethoxy]tetradecane dibromide 1,15 bis [5 (carbobutoxymethyl dimethyl ammonium)-butoxy] -pentadecane dibromide 1,16 bis [/3 (carbomethoxymethyldimethylammonium)-ethoxyl-hexadecane dibromide 1,16 bis [,8(carboisoamyloxyrnethyl dimethyl ammonium) -ethoxy] -hexadecanedibromide 1,16 bis [,8 (carbohexyloxymethyl piperidinium)-ethoxyl-hexadecane dibromide 1,16 bis [13.- (carboisopropoxymethyldimethylammonium) -ethoxy] -heXadecane dibromide 1,18 bis [B(carbomethoxymethyl diethyl ammonium)-ethoxy]-octadecane dibromide 1,20bis [B (carboethoxymethyl dimethyl ammonium -ethoxy] -eicosane dibromideWhat We claim is: r 1. A diammonium compound of the formula R C|3H2COORI ROOO.CH2 R 0983 N (CH2)m 'O (OH2)n O (CH2)m-N .2An

wherein 2. 1,10 bis 3 (dimethyl carbethoxymethylammonium)ethoxy]-decanedibromide.

3. 1,10 bis [B (dimethyl cartobutoxymethylammonium)-etho: yl-decanedibromide.

References Cited in the file of this patent UNITED STATES PATENTS2,101,524 'Balle et a1. Dec. 7, 1937 2,667,493 Slack Jan. 26, 1954'Goldberg et al. Feb. 9, 1954

1. A DIAMMONIUM COMPOUND OF THE FORMULA